A cyclin-dependent kinase (CDK) belongs to a serine/threonine protein kinase, and is mainly involved in cell cycle regulation. For example, CDK1, CDK2, CDK4 and CDK6 are involved in the regulation of cell cycle progression and checkpoint. Besides, CDK8 and CDK9 are involved in the regulation of cell transcriptional activity. Cyclin activates kinase activity of CDKs by binding to the CDKs, and phosphorylates downstream substrates to participate in the regulation of cell cycle. Different CDKs bind to specific cyclins. Wherein CDK4 and CDK6 are activated by binding to a protein of Cyclin D family, and then phosphorylate a downstream RB protein, thereby relieving the inhibitory effect of RB on a transcriptional factor E2F, and thus activating its transcriptional activity, resulting in transition of the cell cycle from G1 phase to S phase.
No matter the defect of pRB or abnormality of its regulatory factor can cause cell hyperproliferation, which is very common in tumors. About 80% tumor cells have normal pRB. In most cases, malignant proliferation of a tumor is caused by regulatory factor abnormality of a RB signal pathway. For example, excessive nucleus metastasis of a protein of cyclin D family results in inactivation of RB in mantle cell lymphoma and multiple myeloma; cyclin D is overexpressed in breast cancer and esophageal squamous cell carcinoma; CDK4 can be overexpressed in liposarcoma; and p16 has defects in melanoma, non-small cell lung cancer and pancreatic cancer. Thus, the goal of inhibiting tumor growth may be achieved by inhibiting the kinase activity of CDK4/CDK6, and its effectiveness has been validated in many cancer models in vitro and in vivo, the inhibition of its activity can block the cell cycle at G1 phase, thereby inhibiting tumor growth. Furthermore, a mouse knockout model shows that knockout of CDK4 or CDK6 has little effect on the growth and development of animals, and abnormalities occur only in individual organs, while knockout of CDK1 results in embryo deaths. Therefore, compared with a broad spectrum inhibitor of CDKs family, an inhibitor selectively targeting CDK4/CDK6 may have a greater therapeutic window.
WO2010020675 discloses a compound ribociclib (also known as LEE011) as a CDK4/CDK6 inhibitor, which is developed by Novartis, and has entered phase III clinical trials at present.
